Shortening of hospital stay and improving survival in patients with chronic kidney disease

ABSTRACT

Formulations containing a Vitamin D compound or analog, such as paricalcitol (Zemplar™) are useful for shortening hospital stays in chronic kidney disease patients with or without hyperparathyroidism. Also disclosed are methods of shortening hospital stays for chronic kidney disease patients with or without hyperparathyroidism, and methods for determining reduction length of hospital stay in chronic kidney disease patients with or without hyperparathyroidism. Titration to serum calcium or serum PTH is avoided by use of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to the provisional Application No.60/403,930 filed on Aug. 16, 2002 and to the provisional Applicationentitled Improved Hospitalization Outcomes In Hemodialysis PatientsTreated With Paricalcitol, filed May 13, 2003 as attorney docket no.7066.US.Z1.

FIELD OF THE INVENTION

This invention is generally directed to formulations containing VitaminD compounds or Vitamin D analogs, especially paricalcitol, which areuseful to shorten hospital stays and improve survival in patientsreceiving chronic renal replacement therapy. The invention also relatesto methods of shortening hospital stays for patients with chronic kidneydisease, and methods for determining reduction length of hospital stayin patients with chronic kidney disease.

BACKGROUND OF THE INVENTION

Approximately half of the thousands of patients receiving chronic renalreplacement therapy suffer from secondary hyperparathyroidism, which isoften accompanied by skeletal abnormalities, cardiovascularcomplications, infections and immunoregulatory dysfunction, foot andextremity complications, anemia, or some combination of the foregoing.These patients are at increased risk for fracture calciphylaxis andcardiovascular events, all of which may result in lengthy hospitalstays, morbidity, and mortality, which can be magnified by abnormalitiesin serum calcium and phosphorus. While Vitamin D compounds or analogscan reverse hyperparathyroidism, they can affect calcium and phosphorushomeostasis. Different compounds can modulate serum parathyroid hormone,calcium and phosphorus differently, which may affect morbidity andmortality differently.

Our recent data (Dobrez, et al, Nephrology, Dialysis andTransplantation, manuscript accepted) have demonstrated that therapywith paricalcitol (commercially available under the Zemplar® mark fromAbbott Laboratories, North Chicago, Ill.) associates with lowerhospitalizations compared with calcitriol (commercially available underthe Calcijex® mark from Abbott Laboratories, North Chicago, Ill.).FIG. 1. presents ordinary least squares models measuring the impact onall-cause hospitalizations in a subset of paricalcitol patients whoremained exclusively on the initial vitamin D therapy □ compared to theintent-to-treat population ▪. Negative coefficients reflect fewerhospitalizations and hospital days for paricalcitol compared withcalcitriol in both intent-to-treat and monotherapy groups. p<0.0001 forall (n=11,443)

Further, data from others (Teng, et al, New England Journal of Medicine,2003) have shown that patients receiving paricalcitol experience asignificant improvement in survival. These findings are consistent sincemortality is linked with morbidity (Lauska and Kryscio, Neurology, 1994;Keller and Potter, Journal of Gerontology, 1994).

However, neither of these studies was able to differentiate whether thebenefit of decreased mortality and morbidity reflected improvement ofmineral imbalance or an effect of a specific vitamin D therapy. Theauthors report that a survival benefit did not associate with Vitamin Ddose and was independent of baseline serum calcium or phosphorus. Wealso found no dose response associated with hospitalizations and nosignificant difference for mean serum calcium and phosphorus betweencalcitriol and paricalcitol patient groups despite differences inhospitalizations. Further, human studies (Salusky and Goodman,Nephrology, Dialysis and Transplantation, 2002) have suggested thatVitamin D therapy can worsen mortality and morbidity in patients withchronic kidney disease, for example, by causing vascular calcification.Therefore, the medical community has not uniformly endorsed use ofVitamin D compounds in these patients.

Finally, the administration of pharmacological Vitamin D therapyconventionally employs titrating the dose to an effect—correction of PTHand/or serum calcium. Initial doses are based upon patient weight orseverity of disease. Subsequent doses, in addition to titration toeffect, are monitored to avoid overtreatment, e.g., oversuppression ofPTH. All the while, these judicious dose adjustments are achieved whileaverting side effects. Since overtreatment and side effects due toVitamin D therapy appear to affect unfavorable outcomes, as mentioned inthe previous paragraph, these dose titrations are relied on to optimizetherapy.

The majority of the deaths occurring in patients with chronic kidneydisease results from cardiovascular, infectious and/or oncologic causes,regardless of serum PTH. It would be advantageous to reduce themorbidity and mortality of these patients. There is therefore an ongoingneed for an improved treatment regimen for patients suffering from theeffects of chronic kidney disease with or without secondaryhyperparathyroidism, which improved treatment regimen results in shorterhospital stays and subsequent improved survival.

SUMMARY OF THE INVENTION

A first embodiment of this invention, therefore, is directed toformulations containing a Vitamin D compound or analog, especiallyparicalcitol, which are useful for shortening the hospital stay andimproving survival in patients with chronic kidney disease with orwithout secondary hyperparathyroidism compared to chronic kidney diseasepatients not treated with a Vitamin D compound or analog.

A second embodiment of this invention is directed to methods of treatingpatients with a Vitamin D compound or analog, especially paricalcitol,the method providing shortened hospital stays and improving survival inpatients with chronic kidney disease with or withouthyperparathyroidism. Preferred embodiments of this aspect of theinvention do not titrate to serum PTH or serum calcium. Hospital staysand survival are improved compared to chronic kidney patients nottreated with a Vitamin D compound or analog.

A third embodiment of this invention is directed to a method forreducing the length of hospital stays for chronic kidney diseasepatients with or without hyperparathyroidism. According to this aspectof the invention, a therapeutically effective amount of a Vitamin Dcompound or analog-containing formulation is administered to a chronickidney disease patient without titrating to serum calcium or serum PTHlevel. Hospitalizations and hospital days are reduced compared to thosefor a chronic kidney disease patient not receiving a Vitamin D compoundor analog-containing formulation.

Paricalcitol is a preferred Vitamin D compound or analog.

A preferred regimen is equivalent to 4 mcg of paricalcitol or 1 mcg ofcalcitriol administered three times weekly or 2 mcg of paricalcitol or0.5 mcg of calcitriol administered daily.

DETAILED DESCRIPTION OF THE INVENTION

Vitamin D exhibits functions beyond modulation of serum parathyroidhormone, calcium, phosphorus and the resultant bone effects. Vitamin Dmodulates cell differentiation and proliferation in the cardiovascularand immune system, and in various malignant and pre-malignant tissues.Importantly, we found that these broader effects of Vitamin D areindependent of control of serum calcium and phosphorus. As shown in FIG.2, a historical cohort of 11,340 adult patients, new to hemodialysis,was followed over a 35-month period (January 1999 thru November 2001)using a dialysis provider database. Patients entered the cohort at anytime. Vitamin D use was defined by the administration of at least dosesof a Vitamin D product. Hospitalizations were identified by documentedhospitalized absences from the dialysis clinic and were standardized bypatient observation period. ANOVA or Chi-Square tests were used toevaluate differences in baseline characteristics. Univariate tests andnegative binomial regression models were used to evaluatehospitalization outcomes: hospital days per year and hospitalizationsper year.

Analysis revealed that 2,316 patients with baseline characteristics asidentified in Table 1 were treated with paricalcitol (“Par”), 2,299 withcalcitriol (“Cal”), and 6,725 did not receive Vitamin D therapy (“NoD”). “No D” patients did not receive a placebo. Univariate analysesrevealed significant differences at baseline (p<0.0001) amongparicalcitol, calcitriol and No D groups, respectively, (as shown inTable 1) in mean age (62 vs. 64 vs. 65), mean iPTH (558 vs. 419 vs.182), mean calcium (8.4 vs. 8.2 vs. 8.7), mean Ca×P product (44 vs. 41vs. 44), race (42% vs. 33% vs. 19% African American), co-morbidities(40% vs. 33% vs. 35% blood disorders) and geographic region. There wasno difference for baseline phosphorus. Paricalcitol* Calcitriol* NoD*Independent Variables (n = 2,316) (n = 2,299) (n = 6,725) p-ValueClinical Laboratory Values Serum PTH (ng/Ml) 558.4 ± 7.9  418.7 ± 6.3 181.8 ± 2.5  <0.0001 Serum Calcium (mg/dL) 8.45 ± 0.02 8.19 ± 0.02 8.73± 0.01 <0.0001 Serum Phosphorous (mg/dL) 5.19 ± 0.04 5.03 ± 0.04 5.07 ±0.02 <0.0001 Calcium × Phosphorus 43.7 ± 0.3  41.0 ± 0.3  44.1 ± 0.2  NSDemographics Mean Age (years) 61.8 ± 0.3  64.4 ± 0.3  65.4 ± 0.2 <0.0001 Female (%) 48.9 46.8 45.6 0.021 African American (%) 42.1 33.418.7 <0.0001 Co-Morbid Conditions (%)^(†‡) DM Adult Onset DM 48.5 51.552.1 NS Childhood Onset DM 3.6 3.4 3.8 NS No DM 37.4 35.1 34.8 NS DMStatus Unknown 10.5 10.1 9.3 NS Other Endocrine 43.9 41.9 42.0 NSInfectious Disease 3.9 3.0 3.0 NS Neoplasm 3.9 4.3 5.3 NS Hematologic40.4 33.3 35.4 <0.0001 Mental 4.5 4.1 4.8 NS Nervous System 10.2 8.4 9.7NS Cardiovascular 52.3 51.2 52.0 NS Respiratory 6.0 5.6 6.9 NS Digestive9.5 7.7 10.1 NS Genitourinary 30.7 25.3 27.7 NS Pregnancy-Related 0.30.0 0.1 NS Skin 1.5 1.7 2.1 NS Muscle and Bone 5.7 3.9 6.0 NS Congenital1.7 1.4 1.4 NS Trauma/Injury 9.8 7.8 9.9 NSDM = diabetes mellitus,PTH = intact parathyroid hormone*Column totals for individual categories may exceed 100% due torounding.^(†)Per ICD-9 Code^(‡)Patients may have had more than one condition; totals may exceed100%.

Evaluation of hospitalization endpoints revealed median annualhospitalizations for paricalcitol, calcitriol and No D groups (2 vs. 2vs. 3) and median days in the hospital per year (5 vs. 11 vs. 15),respectively. As shown in FIG. 3, negative binomial regression analysisrevealed that patients who did not receive Vitamin D experienced 59%more hospital days per year compared calcitriol group (p<0.0001) and 17%more annual hospitalizations (p<0.006). However, compared to theparicalcitol group, the No D group experienced 30% more annualhospitalizations and 100% more days per year in the hospital (p<0.0001for both)(as shown in FIG. 4).

Patients with chronic kidney disease who did not receive Vitamin Dexperienced more hospitalizations and more days in the hospital comparedto those who were treated with either paricalcitol or calcitriol.Furthermore, patients treated with paricalcitol experienced the fewesthospitalizations and days in the hospital, which may reflect additionalbeneficial effects of Vitamin D compounds and analogs beyond mineral andPTH control.

Suitable patients to be treated according to the invention can havechronic kidney disease with or without hyperparathyroidism. Thus,according to one embodiment, the present invention relates to a methodof treating patients by administering formulations containing Vitamin Dcompounds or analogs. Paricalcitol-containing formulations arepreferred. For example, preferred treatment or preventive regimens forpatients with chronic kidney disease according to the present inventionwould administer therapeutically effective Vitamin D compound oranalog-containing compositions as a bolus dose orally or intravenouslyor as a continuous or sustained dose by depot, transdermal or oralroutes for a sufficient period to improve survival and/or to decreasemorbidity. Suitable delivery forms include but are not limited totablets or capsules for oral administration, injections, transdermalpatches for topical administration (e.g., drug to be delivered is mixedwith polymer matrix adhered to or absorbed on a support or backingsubstrate, e.g. ethylcellulose), depots (e.g., injectable microspherescontaining the desired bioactive compounds) and implants.

The formulations can be administered intravenously or orally at leastthree times weekly. This dose does not require titration to effect—e.g.,correction of PTH or serum calcium, in contrast to conventional VitaminD therapies—since mortality and morbidity are independent to markers ofmineral balance. An exemplary preferred minimum administered dose isequivalent to 4 mcg of paricalcitol or 1 mcg of calcitriol administeredtwo to three times weekly or 2 mcg of paricalcitol or 0.5 mcg ofcalcitriol administered daily. Long term treatment with the formulationsof the invention is possible to maintain the benefits without adverseside effects.

1. A formulation containing a therapeutically effective amount of atleast one Vitamin D compound or analog (for shortening the hospital stayand improving survival in patients with chronic kidney disease with orwithout hyperparathyroidism compared to chronic kidney disease patientsthat are not receiving a Vitamin D compound or analog-containingformulation.
 2. A formulation according to claim 1, wherein said atleast one Vitamin D compound or analog is paricalcitol.
 3. A formulationaccording to claim 1, wherein said at least one Vitamin D compound oranalog is calcitriol.
 4. A formulation according to claim 1, whereinsaid formulation is in injectable dosage form.
 5. A formulationaccording to claim 1, wherein said formulation is in oral dosage form.6. A method of shortening hospital stays and improving survival inchronic kidney disease patients, said method comprising the step ofadministering a composition containing a therapeutically effectiveamount of at least one Vitamin D compound or analog without titrating toserum PTH or serum calcium, wherein hospital stays and survival areshortened compared to chronic kidney disease patients not receiving anyVitamin D compound or analog-containing composition.
 7. A methodaccording to claim 6, wherein said composition is administeredintravenously or orally.
 8. A method according to claim 7, wherein saidcomposition is administered at least three times weekly.
 9. A methodaccording to claim 8, wherein a minimum administered dose is equivalentto 4 mcg of paricalcitol or 1 mcg of calcitriol administered three timesweekly or 2 mcg of paricalcitol or 0.5 mcg of calcitriol administereddaily.
 10. A method according to claim 6 wherein hospital stay isshortened by at least about seven days annually.
 11. A method oftreating a chronic kidney disease patient to reduce hospitalizations andhospital days, comprising the step of: administering a therapeuticallyeffective amount of Vitamin D) compound or analog-containing formulationto said patient without titrating to serum calcium or serum PTH level,wherein said hospitalizations and hospital days are reduced compared tothose for a chronic kidney disease patient not receiving a Vitamin Dcompound or analog containing formulation.
 12. A method according toclaim 11, wherein said patient has hyperparathyroidism.
 13. A methodaccording to claim 11, wherein said formulation comprise paricalcitol.14. A method according to claim 11, wherein said formulation comprisescalcitriol.
 15. A method according to claim 11, wherein said formulationadministered to said patient is equivalent to 4 mcg of paricalcitol or 1mcg of calcitriol administered three times weekly or 2 mcg ofparicalcitol or 0.5 mcg of calcitriol administered daily.
 16. A methodaccording to claim 11, wherein said administering step is conducted viainjection.
 17. A method according to claim 11, wherein saidadministering step is conducted orally.
 18. A method according to claim11, wherein hospitalization is reduced by at least about 7 daysannually.